Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes

Cesarini, Elisa; Mozzetta, Chiara; Marullo, Fabrizia; Gregoretti, Francesco; Gargiulo, Annagiusi; Columbaro, Marta; Cortesi, Alice; Antonelli, Laura; Pelino, Simona Di; Squarzoni, Stefano; Palacios, Daniela; Zippo, Alessio; Bodega, Beatrice; Oliva, Gennaro; Lanzuolo, Chiara

doi:10.1083/jcb.201504035

Cited by 99 publications

(111 citation statements)

References 67 publications

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“…A recent study has also shown that lamin A/C play a role in the compartmentalization and function of the Polycomb group (PcG) of proteins, key regulators of development and differentiation (Cesarini, Mozzetta et al 2015). Depletion of A-type lamins leads to dispersion of PcG proteins, hindering their gene repressive functions.…”

Section: Molecular Mechanisms Behind Cellular Decline In Hgpsmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

217

210

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Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.

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Section: Molecular Mechanisms Behind Cellular Decline In Hgpsmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

217

210

View full text Add to dashboard Cite

show abstract

“…We used an in situ proximity ligation assay (PLA), which is based on the proximity of two antibody-binding events and can detect interactions for a distance of up to 40 nm. As chromatin fibers are expected to be between 10 nm and 30 nm in size, PLA is useful and has previously been used for the study of interactions between histone modifications and nucleosolic lamins (Cesarini et al, 2015). As shown in Fig.…”

Section: Macroh2a Is Required For the Attachment Of Repeats To Lamin B1mentioning

confidence: 99%

“…In the nucleoplasm, lamin A/C further interacts with the surface of polycomb-marked heterochromatin foci (Cesarini et al, 2015). In addition to the nuclear lamina, the nucleolus is the other nuclear structure with a major influence in genome organization and is surrounded by a shell of constitutive heterochromatin (Németh et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Douet

Corujo

Malinverni

et al. 2017

Journal of Cell Science

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Genetic loss-of-function studies on development, cancer and somatic cell reprogramming have suggested that the group of macroH2A histone variants might function through stabilizing the differentiated state by a yet unknown mechanism. Here, we present results demonstrating that macroH2A variants have a major function in maintaining nuclear organization and heterochromatin architecture. Specifically, we find that a substantial amount of macroH2A is associated with heterochromatic repeat sequences. We further identify macroH2A on sites of interstitial heterochromatin decorated by histone H3 trimethylated on K9 (H3K9me3). Loss of macroH2A leads to major defects in nuclear organization, including reduced nuclear circularity, disruption of nucleoli and a global loss of dense heterochromatin. Domains formed by DNA repeat sequences are disorganized, expanded and fragmented, and mildly re-expressed when depleted of macroH2A. At the molecular level, we find that macroH2A is required for the interaction of repeat sequences with the nucleostructural protein lamin B1. Taken together, our results argue that a major function of macroH2A histone variants is to link nucleosome composition to higher-order chromatin architecture.

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“…Hence, in the nuclear space, PcG proteins are organized into aggregates called PcG bodies, mediated by intrinsic and extrinsic protein-protein interactions [ 1 ] whose assembly mirrors the chromatin architecture of PcG clustered targets. Interestingly, recent fi ndings have shown that PcG proteins are also able to crosstalk with the nuclear components [ 5 ], suggesting that the positioning of PcG bodies in the nucleus could be highly regulated.…”

Section: Investigating the Polycomb Group Of Proteins: Technologies àmentioning

confidence: 99%

Polycomb Group Proteins

Lanzuolo¹,

Bodega²

2016

Methods in Molecular Biology

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Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes

Abstract: Reduction of lamin A/C, which is evolutionarily required for the modulation of Polycomb group (PcG) protein–dependent transcriptional repression by sustaining PcG protein nuclear architecture, leads to PcG protein diffusion and to muscle differentiation.

Cited by 99 publications

References 67 publications

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Polycomb Group Proteins

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